1. Field of This Invention
This invention relates to a process for the production of methotrexate, which is N[p-([(2,4-diamino-6-pteridyl)-methyl]N.sup.10 -methylamino)-benzoyl]-L-glutamic acid.
2. Prior Art
The only production method, which is known to have been used on an industrial scale, rests on a condensation of 2,4,5,6-tetraaminopyrimidine with 2,3-dibromopropanol and p-(N-methyl)-aminobenzoylglutaminic acid [see D. R. Seeger et al., J. Am. Chem. Soc. 71, 1753 (1949)]. However, the yield in such case is very low and lies below 6 percent. The product is contaminated with pteridines to such a point that one cannot practically succeed in producing pure methotrexate in an economical manner.
The use of 1,1,3-trichloroacetone instead of 2,3-dibromopropanol produces no essential advantages [see D. C. Suster et al., J. Medic Chemistry 17, 758 (1974)].
An attempt has also been made to synthetize methotrexate by way of 2,4-diamino-6-hydroxymethyl-pteridine. See the following process scheme: ##STR1## The 6-hydroxymethylpteridine may be obtained in accordance with (C. M. Baugh et al., J. Org. Chem. 29, 3610 (1964)) by a complicated and expensive process from 2,4,5,6-tetraaminopyrimidine and dihydroxyacetone in a 50 to 60 percent raw product yield. The easily-accessible tetraaminopyrimidine sulfate at the same time has to first be converted by means of BaCl.sub.2 into its chloride. Furthermore, equimolar quantities of the very expensive, cysteine are used for the cyclization reaction. (According to applicant's own experiments, the product contains about 1/3rd undesirable 6-methylpteridine.)
In a further step, the hydroxymethylpteridine can be converted with thionylchloride into 2,4-diamino-6-chloromethyl pteridine. Because of the sensitivity of the hydroxymethylpteridine, the reaction with SOCl.sub.2 takes a very bad course. The resultant contaminated chloromethylpteridine produces a crude methotrexate in a 7 percent yield (content 60 percent). [See I. N. Duvaz et al., U.S. Pat. No. 3,989,703 (1976)].
The production of the bromomethylpteridine from the 6-hydroxymethylpteridine at about 36 percent yield takes a somewhat selective course. However, the necessity of the use of triphenylphosphine dibromide in a four fold stoichiometric excess as the bromation reagent makes any industrial use of the process more difficult [see J. R. Piper et al., J. Heter. Chem. 11, 279, (1974)].
The halomethylpteridines for their part can then be converted with p-(methyl)-aminobenzyl glutamic acid into methotrexate.
Finally, a way via pyrazine systems is known [see M. Chaykowsky, J. Medic, Chem. 17, 1212 (1974)].
Diketene and malonitrile are converted in two steps into 2-amino-3-cyano-5-chloromethylpyrazine-1-oxide and the latter is converted in the presence of phosphorus chloride into 2-amino-3-cyano-5-chloromethyl pyrazine. The latter is converted with p-(N-methyl)-aminobenzoyl-L-glutamic acid and is changed with guanidine in a cyclization reaction into methotrexate.
The great disadvantage of these systems lies in the fact that in the case of the last condensation step, an unavoidable total racemization of the glutamic acid part takes place. Such is very disadvantageous because the D-form of the methotrexate is much less active in the inhibition of tumors [for example, see H. G. Mauthner et al., J. Org. Chem. 40, 3447 (1975)].